Effects on subclinical heart failure in type 2 diabetic subjects on liraglutide treatment versus glimepiride
Effects on subclinical heart failure in type 2 diabetic subjects on liraglutide treatment versus glimepiride both in combination with metforminProduct: / Victoza®
Substance: / Liraglutide
EudraCT Number: / EudraCT nr 2010-022695-31
Sponsor: / Karolinska Institutet, SödersjukhusetAB
Coordinating Investigator: / Johan Jendle
Principal Investigators: / Thomas Nyström, Johan Jendle, Åke Sjöholm, Leif Bojö, Bo Nilsson, Lars-Åke Brodin
Table of Contents
1Administrative Information......
2Background Information......
2.1Trial Rationale......
3Endpoints
3.1Primary Endpoints......
3.2Secondary Endpoints......
4Design......
4.1Outline......
4.2Assessments and Procedures......
4.3Schedule of Investigational Events......
5Selection and Withdrawal of Subjects
5.1Inclusion Criteria......
5.2Exclusion Criteria......
5.3Criteria for Withdrawal......
5.4Subject Log......
6Treatment
6.1Description of Investigational Medicinal Products......
6.2Packaging, Labelling, Storage and Handling of Investigational Medicinal Products......
6.3Treatment Assignment......
6.4Concomitant Medication......
6.5Compliance to Treatment......
6.6Product Accountability and Destruction......
6.7Continuation of Treatment......
7Assessment of Efficacy and Safety
7.1Clinical Efficacy Assessments......
7.2Laboratory Efficacy Assessments......
7.3Laboratory Safety Assessments......
8Proceedings for Adverse Events
8.1Definition of Adverse Events......
8.2Assessment of Adverse Events......
8.3Methods for Eliciting Adverse Events......
8.4Reporting of Adverse Events......
8.5Follow-up of Adverse Events......
9Statistics and Data Management......
9.1Data Management......
9.2Determination of Sample Size......
10Quality Control and Quality Assurance
10.1Monitoring......
11Ethics......
11.1Ethical Conduct of the Trial......
11.2Subject Information and Informed Consent......
12Data Handling and Record Keeping
12.1Case Report Forms......
13Financing and Insurance......
14Publication Policy......
15Supplements......
15.1Amendments......
15.2Personnel Information......
16References......
17Appendices
17.1Schedule of Investigational Events......
17.2SPC Glimepiride30
17.3 SPC Liraglutide 30
Protocol Summary
PROTOCOL IDENTITY AND OBJECTIVESEudraCT Number: / 2010022695-31
Protocol Title: / Effects on subclinical heart failure in type 2 diabetic subjects on liraglutide treatment versus glimepiride both in combination with metformin
Trial Objectives: / To investigate whether liraglutide 1.8 mg QD improves left ventricle longitudinal functional reserve. An18 week,open, assessor-blinded and active-controlled, parallel-group trial.
INVESTIGATIONAL MEDICINAL PRODUCTS (IMP)
Test Product: / Liraglutide
Pharmaceutical Form: / Solution for injection in prefilled pen
Route of Administration: / Subcutaneous (s.c)
Test Product: / Glimepiride
Pharmaceutical Form: / Tablet
Route of Administration: / Oral (p.o)
METHODOLOGY
Trial Design: / Open, assessor-blinded and active-controlled, parallel-group trial, in combination with metformin
Dose/Duration: / 1.8 mg liraglutide QDvs.glimepiride 4 mg QD in total 18 weeks
Primary Endpoint: / Increase in left ventricle longitudinal function and/or functional reserve during rest and after exercise
Efficacy Parameters: / Improvement in left ventricle longitudinal functional reserve, as measured by tissue Doppler echocardiography
Safety Parameters:
POPULATION OF TRIAL SUBJECTS
Description of Trial Subjects: / Type 2 diabetes subjects with an HbA1c above 60 mmol/mol
Number of Subjects: / Eighty (80)
TRIAL TIMETABLE
First Subject In: / 2011
Last Subject In: / 2011
Last Subject Out: / 2012
Abbreviations
Abbreviation / ExplanationAE / Adverse Event
ADR / Adverse Drug Reaction
CRF / Case Report Form
IB / Investigator’s Brochure
ICH / International Conference of Harmonisation
IEC / Independent Ethics Committee
IMP / Investigational Medicinal Products
MPA / Medicinal Product Agency
SADR / Serious Adverse Drug Reaction
SAE / Serious Adverse Event
SPC / Summary of Product Characteristics
SUSAR / Suspected Unexpected Serious Adverse Reaction
1AdministrativeInformation
Thomas Nyström MD, PhD
Karolinska Institutet, Department of Clinical Science and Education Division of Internal
Medicine Södersjukhuset AB, Stockholm, Sweden.
SE-118 83 Stockholm, Sweden
Åke Sjöholm MD, PhD
Karolinska Institutet, Department of Clinical Science and Education Division of Internal
Medicine Södersjukhuset AB, Stockholm, Sweden.
SE-118 83 Stockholm, Sweden
Cristina Häll BMA
Karolinska Institutet, Department of Clinical Science and Education Division of Internal
Medicine Södersjukhuset AB, Stockholm, Sweden.
SE-118 83 Stockholm, Sweden
Johan Jendle MD, PhD
Endocrine and Diabetes Center
Karlstad Central Hospital
SE-65185 Karlstad, Sweden
Bo Nilsson MD, PhD
Department of Clinical Physiology
Karlstad Central Hospital
SE-651 82 Karlstad, Sweden
Leif Bojö MD, PhD
Department of Clinical Physiology
Karlstad Central Hospital
SE-651 82 Karlstad, Sweden
Lars-Åke Brodin MD, PhD
School of Technology and Health
Royal Institute of Technology
Alfred Nobels Allé
SE-14152 Huddinge, Sweden
2
Background Information
Heartdisease, often presenting as cardiomyopathy, is the leadingcause of death among patients with diabetes mellitus [1]. Heart failure in diabetic patients might be due to metabolic disturbances even in the absence of ischemia, e.g. heart failure and cardiomyopathy may be accompanied by the development ofinsulin resistance, both in whole-body and myocardial glucose uptake disturbances[2]. Thespectrum of diabetic heart disease involves a progression fromthe normal heart, to subclinical left ventricular (LV) diastolicand systolic dysfunction, followed by clinically overt symptomaticheart failure. Notably, sub-clinical LV dysfunction is commonin patients with diabetes[3],and the detection of sub-clinicalLV dysfunction in these patients may provide an approach foridentifying high-risk individuals who may benefit from earlierand more active intervention to prevent heart failure[4].Althoughovert LV diastolic and systolic dysfunction can be readily identifiedby conventional diagnostic techniques including echocardiography,the initial stage of myocardial dysfunction may be concealedby various compensatory mechanisms.
Glucagon-like peptide-1 (GLP-1) is a naturally occurring incretinwith insulinotropic properties[5]. Apart from the glycemicactions, cardiovascular effects by GLP-1 have recently been reviewed [6]. Receptors for GLP-1 are expressed in the rodent and human heart and acute activation of GLP-1 signalling has been shown to influence e.g. heart rate and blood pressure [6]. In a knock-out mouse model, GLP-1R-/- mice exhibited a defective cardiovascular contractile response together with left ventricular hypertrophy [7]. GLP-1 improves severe left ventricular heart failure in humanssuffering from a myocardial infarction [8]. Hence, it has been demonstrated that GLP-1 exerts direct functional effects through both GLP-1 receptor dependent and independent pathways in the heart[9].
Native GLP-1 is an extremely short acting peptide, with a half-time breakdown of 1-2 minutes, a feature that makes it unsuitable as a drug treatment for type 2 diabetes. To this end, several long-acting GLP-1 analogues, drugs for treating type 2 diabetes, have been tested for this purpose. The analogue liraglutide exerts its effects via the native GLP-1 receptor, localized not only on the pancreatic β-cells, but also in the human heart. Interestingly, liraglutide has been demonstrated to have beneficial effect on heart function in mice[10]. Taken together, recent data shows that GLP-1 and its stable analogue liraglutide exert beneficial cardiovascular effects.
2.1Trial Rationale
Acutely beneficial cardiovascular effects of GLP-1 on the heart have recently been demonstrated. Therefore the rational for this study is to investigate liraglutide effect on the heart in type 2 diabetic subjects.The 18 week treatment period is expected to be sufficient to evaluate the efficacyand safety of the treatment to be studied. Also, the comparator was chosen due to the fact that glimepiride 4 mg QD has an equal anti-diabetic effects in terms of lowering plasmaglucose as for liraglutide 1.8 mg QD , during a 18 week period[11].In order to obtain the necessary power in the trial, 80 subjects are expected to complete the trial (further described under Determination of sample size, section 9.2).
3
Endpoints
3.1Primary Endpoints
Subjects achieving an absolute increase in left ventricle longitudinal function and/or functional reserve during rest and/or after exercise of 0.7 cm/s, i.e., ΔE’ [1-(1/E’base)] or ΔS’ [1-(1/S’base)]after 18 weeks of liraglutide + metformin, compared with glimepiride + metformin, using tissue Doppler echocardiography.
3.2Secondary Endpoints
The changes from baseline for18 weeks of liraglutide + metformincompared with glimepiride + metformin treatment will improve or affect;
- Global LV function (echocardiography) expressed as ejection fraction (EF)
- Exercise ECG, including working capacity
- 24-hour blood pressure
- Energy delivering from the carotid artery
- N-terminal pro b-type natriuretic peptide (NT-proBNP) levels in serum over time and symptoms of dyspnea or fatigue asassessed by patient and clinician using established scoring systems.
- Gene expression (Affymetrix)
- Plasma markers of inflammation i.e. hsCRP, IL-6, TNF-α and PAI-1
- Plasma markers of endothelial activation i.e. E-selectin, VCAM-1, ICAM-1 and plasma levels of nitrate/nitrite
- Lipids
- HbA1c
- Body weight
- Adverse events in terms of hypoglycaemia
- Quality of life (SF 36)
- Blood test (venipuncture)
4Design
4.1Outline
The present trial is a two centre, open, assessor-blinded and active-controlled, parallel-group trial, in combination with metformin. The trial will compare the treatment with liraglutide 1.8 mg (s.c) QD + metformin up to 1 g BID, with that of glimepiride 4 mg QD (comparator) + metformin up to 1 g BID, on LV function in subjects with type 2 diabetes.
Patients are asked to participate in the study and after informed and written consent has been obtained, subjects will be screened based on the inclusion and exclusion criteria. If needed, subjects will have metformin up-titrated to a maximal daily dose of 2g, or the highest tolerated dose in the run-in period. Total trial duration for the individual subject will be 18 ± 4 weeks. A population of 80 type 2 diabetic subjects will be investigated (Figure 1).
4.2Assessments and Procedures
The subjects will attend a screening visit (Visit 1) in order to assess their eligibility. If found eligible, the subjects will return at Visit 2 within approximately 4 weeks, after Visit 1, with an up-titration with metformin 1 g BID or the maximal tolerated dosage of metformin (Run-in period).
At Visit 2 patients will be tested for;
- Heart function at rest and during an exercise ECG Stress Test with tissue Doppler echocardiography
- 24-hour blood pressure
- Antropometric assessment
- Symptoms of dyspnea or fatigue (scoring system, classified as NYHA).
- Quality of life (SF 36)
- Blood test (venipuncture)
- U-HCG (in fertilized women)
Subsequently thereafter, subjects will during visit 2 be randomized to receive either liraglutide 1.8 mg s.c. (initial dose of 0.6 mg with an up-titration of 0.6 mg every week, final dose 1.8 mg QD) or glimepiride 4 mg p.o (initial dose of 2 mg, with an up-titration of 1 mg every week, final dose 4 mg QD).
At Visit 2, subjects will be supplied with a glucose meter (Abbot Contour) and instruction on use of the device including regular calibration according to the manufacturer’s instruction. Subject will also be provided with written instruction. The glucose meter use test strips calibrated to plasma values. Therefore all glucose measurements performed with drawn capillary blood are automatically calibrated to plasma equivalent glucose values, which will be shown on the display and are the values to be used.
Subjects will be instructed on how to record the results of the self measured plasma glucose (SMPG) values in the meter. Subjects will then ask to monitor a 7 point profile glucose curve consecutively in three days before visit 3, at visit 4 and at the end of treatment (visit 5) and at the end of the trial (visit 6). SMBG values will be transferred via a computerized system (Diasend®).
Visit 3. Telephone visit. Self-reporting glucose measurements.
Visit 4. Telephone visit. Self-reporting glucose measurements.
At week 18 (Visit 5), subjects will be re-tested for:
- Heart function at rest and during an exercise ECG Stress Test with tissue Doppler echocardiography
- 24-hour blood pressure
- Antropometric assessment
- Symptoms of dyspnea or fatigue (scoring system, classified as NYHA).
- Quality of life (SF 36)
- Blood test (venipuncture)
- U-HCG (in fertilized women)
The physician will decide what treatment patients will be continued on Visit 6. Follow up and re-evaluate the anti-diabetic treatment.At all contacts Investigators will ask subject for signs or symptoms of an AE.
4.3Schedule of Investigational Events
Procedures for the scheduled visits and phone contacts are described in the section above and in the flowchart (Schedule of Investigational Events, Appendix 17. 1). Each subject will be followed approximately 18 ± 4 weeks after randomisation.
5Selection and Withdrawal of Subjects
5.1Inclusion Criteria
1Type 2 diabetes.
2Heart Failure, visualized with echocardiography, one of the following (2.1, 2.2 or 2.3).
2.1Ejection Fraction ≤ 50%.
2.2Decreased systolic velocity (four chamber view) where two, out of four segments (Septum, Lateral, Inferior and Anterior Wall) has a relative decrease in velocityof 20% compared to a normal population.
2.3Evidence of diastolic dysfunction as shown by abnormal left ventricular relaxation, filling, diastolic distensibility or stiffness. An E/E’ ratio (ratio of early diastolic velocities of mitral inflow derived Doppler imaging and myocardial movement derived by tissue Doppler imaging) >15 is considered diagnostic of diastolicdysfunction and an E/E′ ratio < 8 as diagnostic of theabsence of diastolic heart failure. An increased left atrial size (>49 ml/ m2) and anincreased left ventricular mass (>122 g/m2 in women and >149 g/m2 in men) are considered sufficient evidence ofdiastolic dysfunction when the E/E′ ratio is inconclusive.
3HbA1c(accordingly to IFCC) 60 mmol/mol –95 mmol/mol.
4If antihypertensive treatment, the medication has to be stable, no change, for the last 1 month.
5Male and female subjects, 18-70 years of age.
6Signed informed consent form.
5.2Exclusion Criteria
- Type 1 diabetes (autoantibody positive).
- Any history of receiving GLP-1 analogues or dipeptidyl peptidase inhibitors (DPP-IV inhibitor) or glimeperid.
- Previous treatment with glitazones within 6 months.
- Previous treatment with other sulphonylureawithin 3 months.
- Previous treatment with insulin (any regimen) within 1 month.
- Known severe heart failure, classified as NYHA 3-4.
- Significant ischemic heartdisease (defined as angina-limited exercise or unstable angina); documentedacute myocardial infarction (MI) within the previous 8 weeks.
- Active myocarditis; malfunctioning artificial heart valve.
- Atria fibrillation or flutter
- History of ventricular tachycardia within 3 months beforestudy entry; second- or third-degree atrioventricularblock.
- Implanted pacemaker.
- Supine systolic blood pressure <85 mm Hg or >200 mm Hg.
- Primary renal impairment (creatinine clearance < 30 ml/min), or creatinine clearance < 60 ml/min if treated with metformin.
- Uncorrected hypokalemiaor hyperkalemia (potassium <3.5 mmol/l or >5.5 mmol/l).
- Significant anemia (Hb < 90 g/l)
- Treatment with another investigational agent within 30 days beforestudy entry, judged by the investigator.
- Severe gastrointestinal disease, including gastroparesis. As judged by the investigator.
- Body mass index (BMI) 40 kg/m2.
- Malignant neoplasm requiring chemotherapy, surgery, radiation or palliative therapy in the previous 5 years. Patients with intraepithelial squamous cell carcinoma of the skin treated with topical 5FU and subjects with basal cell skin cancer are allowed to enter the trial.
- Females of child bearing potential who are pregnant, breast-feeding or intend to become pregnant or are not using adequate contraceptive methods (adequate contraceptive measures as required by local law or practice).
- Current drug and alcohol abuse.
- History of acute or chronic pancreatitis
- Subjects considered by the investigator to be unsuitable for the study.
- Criteria for Withdrawal
The subjects may withdraw at will at any time. The subjects may be withdrawn from the trial at the discretion of the Investigator due to safety concerns or if judged non-compliant with trial procedures. Subjects randomised in error must be withdrawn from the trial
A subject must be withdrawn if the following applies:
- Pregnancy or intention of becoming pregnant
- Participation in other trials throughout the trial
- Serious heart failure or a cardiovascular event
- Subject Log
All subjects in the screeningprocess will be documented in a medical chart accordingly to their inclusion criteria or exclusion criteria.
6Treatment
All subjects have been instructed to up-titrate metformin to 1 g BID, or maximal tolerated dose of metformin, before randomisation (run-in period). At randomisation (Visit 2) subjects will be randomised into one of the two treatment groups; liraglutide 1.8 mg (s.c) QD (initial dose of 0.6 mg with an up-titration of 0.6 mg every week, final dose 1.8 mg) or glimepiride 4 mg (p.o) QD (initial dose of 2 mg, with an up-titration of 1 mg every week, final dose 4 mg), both in combination with metformin 1 g BID.
Subjects will be instructed to take metformin meanwhile the breakfast and the dinner meal.
Subjects will be instructed to take glimepiride before the breakfast meal and liraglutide at the same time point every day.
6.1Description of Investigational Medicinal Products
Liraglutide will be available as a solution for injection at a concentration of 6.0 mg/ml, supplied in a 3 mL pre-filled disposable pen.
Glimepiride will be available as tablet for oral administration, each tablet containing 1 mg, 2 mg or 4 mg of glimepiride.
6.2Packaging, Labelling, Storage and Handling of Investigational Medicinal Products
The trial products will be packed and labelled by an external clinical supply contractor, which can be done since both trial products are commercially available.Labelling will be in accordance with Annex 13, local law and trial requirements.
Each investigator site will be supplied with sufficient trial products for the trial.
Trial product will be packed in dispensing units and will be distributed to the sites according to enrolment and randomisation.
The trial products will be dispensed to each subject at Visit 2, as required according to treatment group. The randomisation procedure will allocate trial product Dispensing Unit Number (DUN) to the subject at the dispensing visit. The correct DUN must be dispensed to the subject at the dispensing visit.
Instruction to the subject on how to use the trial liraglutide pre-filled disposable pen should be provide by the Investigator at Visit 2.
The trial products should be stored in accordance with the storage conditions as stated in the Summary of Product Characteristics for each product, see Appendices 17.2 and 17.3.
The Investigator must ensure availability of proper storage conditions, and record and evaluate the temperature (at least every working day). Storage facilities should be checked frequently. A log to document the temperature must be kept.
Storage and in-use conditions:
Liraglutide
Not in use: The liraglutide pre-filled pen must be stored in a refrigerator at a temperature between +2°C and + 8°C. Keep away from the cooling element. Do not freeze and do not use if it has been frozen.
In-use: After first opening the liraglutide pre-filled pen can be stored for one month at temperatures below +30°C or in a refrigerator between +2°C and +8°C.
Do not freeze and do not use if it has been frozen.
The pen must be protected from all sources of light, and the pen cap should be kept on when the pen is not in use. The liraglutide should not be used if it does not appear clear and colourless.
Glimepiride
Store at temperatures below +30°C. Store in original package. Sensitive to damp.
In case of incorrect storage, the site staff should inform the Principal Investigator without delay. The trial products must be set on-hold until notified by Principal Investigator.
No trial product should be dispensed to any person not enrolled in the trial.
6.3Treatment Assignment
The study is an open, assessor-blinded and active-controlled, parallel-group trial.
Randomisation will be carried out in a (1:1) manner using an interactive voice/web response system (IV/WRS) to randomise subjects into the treatment groups:
- Liraglutide QD or
- Glimepiride QD
both in combination with metformin.
6.4Concomitant Medication
Type 2 diabetic patients with metformin, as a single oral anti-diabetic drug, or diet controlled, will be eligible for the study.